Piperidine compounds and process for providing the same

Abstract

The tosylate ester of the formula (6) and its salts, are convenient intermediates in the synthesis of paroxetine.

1 . A (−)trans-4-(p-fluorophenyl)-3-(p-toluenesulfonyloxymethyl)-1-methyl-piperidine of the formula (6),  
       
         
           
           
               
               
           
         
       
       or a salt thereof.  
     
     
         2 . The compound according to  claim 1 , wherein said compound is in a solid state.  
     
     
         3 . The compound according to  claim 2 , wherein said compound is in a crystalline state.  
     
     
         4 . The compound according to  claim 3 , wherein said crystalline compound contains 0.2% or less of a des-fluoro impurity thereof.  
     
     
         5 . A process which comprises: reacting a compound of formula (1) or a salt thereof:  
       
         
           
           
               
               
           
         
       
       with a tosylate moiety-providing compound to form a compound of formula (6):  
       
         
           
           
               
               
           
         
       
     
     
         6 . The process according to  claim 5 , wherein said tosyl moiety-providing compound is a tosyl-halide.  
     
     
         7 . The process according to  claim 6 , wherein said tosyl-halide is p-toluene sulfonyl chloride.  
     
     
         8 . The process according to  claim 5 , wherein said reacting is carried out in a solvent.  
     
     
         9 . The process according to  claim 8 , wherein said solvent is ethyl acetate.  
     
     
         10 . The process according to  claim 8 , wherein said reacting is carried out in the presence of an organic base.  
     
     
         11 . The process according to  claim 10 , wherein said base is triethylamine or pyridine, and said base is present in an amount within the range of 1.0-1.5 times the molar amount of said tosyl moiety-providing compound.  
     
     
         12 . The process according to  claim 5 , wherein said reacting is carried out at a temperature within the range of 0-80° C.  
     
     
         13 . The process according to  claim 5 , which further comprises isolating said compound of formula (6) as a solid material.  
     
     
         14 . The process according to  claim 13 , which further comprises crystallizing said solid compound of formula (6) from methanol, ethanol, or isopropanol.  
     
     
         15 . The process according to  claim 5 , which further comprises converting said compound of formula (6) to paroxetine or a pharmaceutically acceptable salt thereof.  
     
     
         16 . The process according to  claim 15 , wherein said converting comprises reacting said compound of formula (6) with sesamol to form methylparoxetine; reacting said methylparoxetine with phenylchloroformate to form a carbamate; and treating said carbamate with alkali to form paroxetine.  
     
     
         17 . The process according to  claim 16 , which further comprises processing said paroxetine to form paroxetine hydrochloride or paroxetine mesylate.